Clinical features of dystonia
Literature search on the clinical features of dystonia identified a report of a multidisciplinary working group , one workshop report , 64 primary studies on clinically based diagnosis and 125 primary studies on the diagnostic accuracy of different laboratory tests. The primary clinical studies encompassed 4 cohort studies, 15 case–control studies, 12 cross-sectional and 33 clinical series.
The clinical features of dystonia have been summarized in the previous guidelines edition . More recent reviews and new primary studies have focused on specific diagnostic features; a recent review has assembled the features of dystonia into a diagnostic flowchart .
Dystonia is a dynamic condition that often changes in severity depending on the posture assumed and on voluntary activity of the involved body area. The changing nature of dystonia makes the development of rating scales with acceptable clinimetric properties problematic.
Three clinical scales are available for generalized dystonia: the Fahn–Marsden rating scale , the Unified Dystonia Rating Scale and the global dystonia rating scale . The total scores of these three scales correlate well, they have excellent internal consistency, from good to excellent inter-rater correlation and from fair to excellent inter-rater agreement . An evidence-based review identified more than 10 rating scales for cervical dystonia . However, the most frequently used ones are the Toronto Western Spasmodic Torticollis Rating Scale , the Tsui scale  and the Cervical Dystonia Severity Scale .
Dystonia influences various aspects of quality of life, particularly those related to physical and social functioning. Class IV studies have evaluated the predictors of quality of life in dystonia [12,16]. Functional disability, body concept and depression were important predictors of quality of life in dystonia.
The classification is based on three axes: (i) aetiology, (ii) age at onset of symptoms, and (iii) distribution of body regions affected (Table 1). The etiological axis defines primary (idiopathic) dystonia with no identifiable exogenous cause or evidence of neurodegeneration (i.e., no progressive loss of neural cells). In the pure form, dystonia is the only clinical sign (apart from dystonic tremor). We propose to call these forms ‘primary pure dystonia’ (PPD). In dystonia plus, instead, usually there are additional movement disorders (e.g., myoclonus or parkinsonism). In the paroxysmal form, symptoms are intermittent and provoked by identifiable triggers (e.g., kinesigenic because of sudden movement, exercise-induced or non-kinesigenic). Non-primary dystonia is because of heredodegenerative diseases or secondary (symptomatic) to known causes; these forms are characterized by the presence of additional symptoms or signs, apart from movement disorders. A number of genes and gene loci have been identified for primary as well as for other forms.
Use of genetic test in diagnosis and counselling
Two genes for PPD have been identified: DYT1 and DYT6 [17,18]. Three other gene loci for autosomal-dominant PPD (DYT4, DYT7 and DYT13) and two forms of recessive PPD (DYT2 and DYT17) have been described with phenotypes ranging from cranial to generalized dystonia; however, the specific gene abnormality has not yet been identified .
All known DYT1 mutations reside in exon 5 of the TorsinA gene, except for one in exon 3 . Screening for a GAG-deletion at position 302/303 is sufficient for clinical testing (class II) . Only two patients with PPD have been described with missense mutations in exon 3 (p.F205I) and exon 5 (p.R288Q), and the pathogenicity of this variant has not been proven, as no familial cosegregation has been demonstrated [20,22].
Early-onset DYT1 dystonia typically presents in childhood and usually starts in a limb, gradually and in many patients rapidly progressing to a generalized form (class II) . Many exceptions to this typical presentation have been reported, especially in mutation carriers from DYT1 families with focal or segmental dystonia of adult onset (class IV) [23,24]. Family studies have assessed that the penetrance of DYT1 dystonia is around 30%.
DYT1 mutations are the most important genetic cause of early-onset PPD worldwide. Phenotype-genotype correlations have been assessed in different DYT1 dystonia populations (class II and III) [21,25]. In Ashkenazi Jews, DYT1 testing is positive in close to 100% in patients with limb onset dystonia before age 26. Recommendation 1 below is based on such evidence [21,26]. In the western-European population, the proportion of DYT1 mutation negative dystonia is considered higher than in North America . Patients with early-onset PPD not caused by the DYT1 gene tend to have later age at onset, less commonly limb onset, more frequent cervical involvement, and a slower progression than DYT1 PPD cases (class IV)  In patients with generalized dystonia with cranio-cervical onset DYT6 mutations should be considered . thanatos associated protein (THAP1) has been identified to cause autosomal-dominant DYT6, ‘mixed’-type dystonia, in Amish-Mennonite families with cranial or limb onset at young age (from 5 to 48 years) [18,29]. DYT6 mutations have been described in other populations with clinical presentations from focal to generalized dystonia in a few per cent of cases. In particular, early-onset generalized PPD with spasmodic dysphonia is a characteristic phenotype caused by DYT6 mutations (class IV) .
Four dystonia-plus syndromes have been characterized genetically: dopa-responsive dystonia (DRD, DYT5), myoclonus-dystonia (M-D, DYT11), rapid-onset dystonia-parkinsonism (RDP, DYT12) and autosomal-recessive (AR) dystonia-parkinsonism (DYT16).
The most common form is DRD linked to the GTPcyclohydrolase I (GCH1) gene. As this is a treatable and often misdiagnosed condition, a particular effort should be made to establish a correct diagnosis. The classical phenotype comprises onset with walking difficulties before 20 years, and progression to segmental or generalized dystonia, sometimes with additional parkinsonism and sustained response to levodopa [30,31]. Three additional DRD categories with different courses have been recognized: (i) young-onset (<20 years) cases with episodic dystonia, toe walking or progressive scoliosis throughout life; (ii) compound heterozygous GCH1 mutation carriers, who develop young-onset severe DRD with initial hypotonia similar to AR-DRD caused by tyrosine hydroxylase (TH) mutations; and (iii) adult-onset DRD patients manifesting above age 30 with mild dystonia or resting tremor or non-tremulous parkinsonism [31,32]. To date numerous GCH1 mutations but no phenotype-genotype correlations to specific heterozygous GCH1 mutations have been detected.
Inclusion of screening for gene dosage alterations of GCH1 [33,34] in addition to direct sequencing has increased the rate of detected mutations to over 80% [35,36].
If genetic testing of GCH1 is negative, other genes of the tetrahyhdrobiopterin and dopamine synthesis pathways like TH and sepiapterin reductase should be considered, especially if inheritance is recessive or atypical features like mental retardation or oculogyric crises are present (class IV) [36,37]. Parkin mutations are a rare differential diagnosis of DRD, and the diagnosis can be made by dopamine transporter imaging (class IV) . For the TH gene, sequencing of the 3′-promoter sequence is recommended to increase mutation detection (class IV) .
A therapeutic trial with levodopa has been proposed for diagnostic purposes (class IV) . Alternatively, studies on pterin and dopamine metabolites from cerebrospinal fluid (CSF) or a phenylalanine loading test have been suggested as diagnostic complements [41–43], but there is no clear evidence regarding their diagnostic accuracy and both may only be performed in specialized centres. Hence, the practical recommendation still remains that every patient with early-onset dystonia without an alternative diagnosis should have a trial with levodopa. The initial symptoms at the onset of M-D emerge in childhood and usually consist of lightning jerks and dystonia mostly affecting the neck and the upper limbs, with a prevalent proximal involvement and slow progression . In a subset of patients, M-D presents as a gait disorder with lower limb onset and evolves into the typical clinical presentation until adolescence [45,46]. Myoclonus and dystonia are strikingly alleviated by alcohol in many but not in all patients . However, a response to alcohol is not specific for DYT11 (class IV)[48–50]. In patients with the typical M-D phenotype, mutations in the epsilon-sarcoglycan gene (DYT11) may be detected in over 50% with an age at onset generally below 20 [51–54]. As in DRD, the rate of mutation detection in the epsilon-sarcoglycan gene is increased by screening for exon or whole gene deletions (gene dosage) [50,55–57]. Complex phenotypes with additional features may be related to chromosomal deletions and rearrangements of the 7q21 region [50,57–59].
In DYT12, RDP, the mutated gene is ATP1A3. RDP is an extremely rare disease with onset in childhood or early adulthood in which patients develop dystonia, bradykinesia, postural instability, dysarthria and dysphagia over a period ranging from several hours to weeks with triggering factors . In addition to rapid onset, features suggesting an ATP1A3 mutation are prominent bulbar symptoms and a gradient of dystonia severity with the cranial region being more severely affected than arms and legs. Tremor at onset or prominent pain could not be found in ATP1A3 mutation-positive patients .
Protein-kinase RNA-dependent activator (PRKRA) has been identified as the DYT16 gene on chromosome 2q31.2. Mutations cause a novel form of non-degenerative, early-onset AR dystonia-parkinsonism . The phenotypic spectrum of DYT16 has not been determined yet.
Four forms of paroxysmal dystonias have been genetically defined to date. In two, only the locus has been mapped: paroxysmal dystonic choreoathetosis with episodic ataxia and spasticity (DYT9) and paroxysmal familial kinesigenic dyskinesia (DYT10). Paroxysmal non-kinesigenic dystonia (PNKD, DYT8) is caused by mutations in the myofibrillogenesis regulator 1 (MR-1) gene in all families with a typical PNKD phenotype [63–65]. This condition is characterized by episodes of choreodystonia with onset in infancy or early childhood. Attacks typically last 10 min–1 h and are induced by caffeine or alcohol .
Paroxysmal exertion-induced dyskinesia (PED) is caused by mutations in the gene for the glucose transporter 1 (SLC2A1, DYT18). In addition to PED, patients with DYT18 gene may present with epilepsy (absence or generalized tonic-clonic seizures), migraine, cognitive deficits, haemolytic anaemia or developmental delay. A diagnostic marker is a decreased CSF/serum glucose ratio below 0.5 (class III) [67,68].